SV40 large T Antigen (T) forms complexes with the product of the retinoblastoma gene (RB), a known tumor and growth suppressor. Complex formation is essential for full T transforming function. Underlying this is evidence showing that, upon binding, T down modulates one or more aspects of the growth suppression function of RB. RB growth suppression function is, at least in part, a product of specific interactions with a group of cellular proteins which bind to an internal RB protein receptor domain called the 'pocket.' One of these proteins is the transcription factor, E2F, a growth promoting element responsible for activating a number of genes whose products are essential for exit from G0/G1 and passage through S. Unphosphorylated RB, T releases E2F from the RB pocket, enhancing its activity and simultaneously promoting passage of a G1-arrested cell into S. This proposal is aimed at better understanding how RB operates biochemically and, in particular, at gaining new insights into the nature of the full RB tumor suppression function. In particular, the work will attempt to understand the significance of RB interactions with a newly cloned RB binding protein, RBAP-2. It will search for evidence that RB functions after it is phosphorylated. It will attempt to learn whether RB has transformation suppression functions beyond its ability to stop growth in G1. An effort to probe the potential role of the N-terminal 378 aa of RB will be initiated, since this region is suspected of contributing to RB functions other than G1 growth suppression. Finally, the significance of a recently detected interaction between RB and the oncogene product, mdm2, a known suppressor of p53 growth regulatory function will be pursued. The ultimate goal of the work is to understand how the T-RB interaction contributes to SV40 tumorigenesis.